br Only one previous study has reported
Only one previous study has reported on associations between the non-metallic air toxics and breast cancer risk on a US-wide scale (Hart et al., 2018). In the Nurses' Health Study II (NHSII), 1,2-dibromo-3-chloropropane was the only air toxic that demonstrated a consistent increased risk of breast cancer (HRquartile 4vs1 = 1.12; 95% CI: 0.98–1.29; p-trend = 0.004). Although in our study there was a sug-gestive association in the 3rd quintile of 1,2-dibromo-3-chlorpropane (HR = 1.09; 95% CI: 0.97–1.19), there was no evidence of a monotonic trend and the magnitude was not as strong as for other air toxics. The NHSII found additional suggestively elevated risks for overall or ER+ breast cancer for 1,3-butadiene, 2,4-dinitrotoluene, 2,4-toluene diiso-cyante, benzene, carbon tetrachloride, hydrazine, nitrobenzene, pro-pylene oxide, and vinylidene chloride. We similarly found an increased risk for 2,4-toluene diisocyanate (quintiles 2 and 3) and ER+ breast cancer, but not the others. Diﬀerences in approaches between the NHSII and our study reported here could explain the diﬀering results. The NHSII utilized the 2002 NATA, whereas the 2005 version was used in our study. The 2005 version included multiple updates to improve upon the exposure assessment in earlier versions (including use of an up-to-date NEI with more recent information on industrial and other sources, use of HEM with AERMOD (a refined dispersion model) for more source types, and a new dataset for airport-related emissions with 5-times as many airports (Environmental Protection Agency, 2011)). Additionally, the follow-up for the NHSII was conducted from 1989 to 2011, whereas Sister Study follow-up was from 2003 to 2009 through 2016. Therefore, changes in air toxics levels or distributions over those periods could partially explain the diﬀerences between the two studies.
A previous study that also used the Sister Study Necrosulfonamide reported that metal air toxics, particularly mercury, cadmium, and lead, were associated with an increased risk of postmenopausal breast cancer in individual pollutant models and as a mixture using a weighted quantile sum (White et al., 2018). Together, the results from both of these Sister Study-based studies support an association between some air toxics, metallic or non-metallic, and breast cancer risk.
Limitations of our study relate to exposure misclassification from NATA. Concentrations at the census tract level do not fully account for variation in an individual's daily activities that could lead to higher or lower exposure, and all women within a census tract are assigned the same concentration. Although NATA captures many ambient sources that are a major contributor to an individual's exposure, exposure to some air toxics can also come from cigarette smoke, occupation, indoor air, and drinking water; sources not captured by NATA. Finally, the air toxics levels from NATA were linked to Sister Study women's baseline residential addresses, so an assumption of our study is that these levels represent those from relevant etiologic exposure periods for breast cancer or that recent exposure is an important window. Given that NATA air toxic concentration estimates represent a one-year average (Environmental Protection Agency, 2011) they may be indicative of a long-term or typical, rather than acute, exposure. The Sister Study po-pulation has been residentially stable; nearly half of the population had lived in their baseline address for at least 10 years and 80% have
remained in that address throughout follow-up. This increases the likelihood that the residential levels at baseline reflect past residential levels and those until diagnosis.
The Sister Study is a fairly homogenous population composed mostly of women who are non-Hispanic White, well-educated, and postmenopausal. Further, these women have a family history of breast cancer. These aspects do not aﬀect the internal validity of our study results, but may limit generalizability to other groups.
This study has a number of strengths. The Sister Study is a large, prospective cohort, which provided suﬃcient study power to examine the main air toxic-breast cancer associations as well as modification of these associations by obesity and physical activity. Additionally, these Sister Study participants came from all 50 US states which allowed us to examine nationwide associations and have a larger range of exposure upon which to estimate associations compared to focusing on a popu-lation limited to one state or geographic region. We used the 2005 NATA, which had undergone a number of modeling improvements to increase the scope and improve the modeling techniques compared to the 1996, 1999, and 2002 versions (Environmental Protection Agency, 2011). Further, given that NATA provides the only available nation-wide data on air toxics, it is a valuable resource. Ours is the first study to comprehensively examine physical activity and BMI as eﬀect modi-fiers for these air toxics with breast cancer risk and the first to explore multipollutant combinations that could be relevant for further ex-amination. Further, we conducted a large number of sensitivity ana-lyses and found that our primary results were robust to factors such as adjustment for residential region, restriction to non-Hispanic whites, and restriction to those that lived in their baseline address > 10 years.